Effective agrochemicals are essential to maintaining sustainable agriculture to support a growing population. Herbicide resistance is an ever increasing problem, and in order to combat this there is a requirement for the introduction of new herbicidal agents with novel modes of action. Natural products serve as an abundant source of structurally diverse phytotoxins, which typically have novel modes of action in comparison with their synthetic counterparts. The natural product coronatine (COR), isolated from Pseudomonas syringae, has been a compound of interest to the agrochemical community since its isolation and elucidation of its phytotoxic properties. Through the industry/academia collaboration described in this thesis, coronatine is now a tractable target for a structure-activity relationship (SAR) campaign. Through the development of a scalable synthesis of the COR polyketide fragment, coronafacic acid (CFA), a diverse array of N-coronafacoyl-amino acid analogues were synthesised. The inherent flexibility of the synthesis, imparted by its convergent nature, has enabled the synthesis of several CFA analogues, featuring single point changes to the parent scaffold. In the complementary study, scalable synthesis of the COR amino acid moiety, coronamic acid (CMA), enabled diverse screening of analogues where the core moiety was varied. Through the biological evaluation of these compounds, an SAR for herbicidal activity around the COR scaffold has been identified. Initial efforts focused on modification of the amino acid component, however work in this area failed to afford any compounds of significant activity. Retention of the COR amino acid moiety, CMA, with modification of the CFA core has generated several COR analogues with good levels of potency.On analysis of this data set and supporting computational docking, we have concluded that the key convenor of potency in COR is the amino acid fragment, CMA. The CFA moiety appears to be comparatively more amenable to structural modification with the retention of potency, and we suggest that further SAR studies of the COR scaffold focus on analogues of this unit.
|Date of Award||1 Nov 2017|
- University Of Strathclyde
|Supervisor||Allan Watson (Supervisor) & Craig Jamieson (Supervisor)|